Aortic Valve Disease 3

A number sign (#) is used with this entry because of evidence that aortic valve disease-3 (AOVD3) is caused by heterozygous mutation in the ROBO4 gene (607528) on chromosome 11q24.

Description

Aortic valve disease-3 (AOVD3) is characterized by aortic stenosis and/or bicuspid aortic valve (BAV), associated in some patients with aneurysm of the aortic root and/or ascending aorta. Atrial septal defect (ASD) has also been observed in some individuals (Gould et al., 2019).

For a general phenotypic description and a discussion of genetic heterogeneity of aortic valve disease, see AOVD1 (109730).

Clinical Features

Gould et al. (2019) studied a family (family 1) in which 7 males and 1 female over 3 generations had aortic root aneurysm, which was isolated in 4 patients and associated with aneurysm of the distal ascending aorta as well as aortic valve stenosis (AS) in 3; the remaining patient had associated bicuspid aortic valve with a right noncoronary cusp fusion pattern, as did 1 of the patients with AS and ascending aortic aneurysm. Three family members had undergone aortic valve replacement. In addition, the authors studied a mother and son (family 2) with aortic valve stenosis and atrial septal defect; the son also exhibited BAV with a left-to-right fusion pattern.

Molecular Genetics

By whole-exome sequencing in a cohort of 9 families with bicuspid aortic valve and/or thoracic aortic aneurysm (AAT), who were negative for mutation in AAT-associated genes, Gould et al. (2019) identified 2 families with heterozygous mutations in the ROBO4 gene: in family 1, a splicing mutation (607528.0001) was present in 8 affected individuals as well as in 2 unaffected family members; in family 2, an affected mother and son were heterozygous for a missense mutation (R64C; 607528.0002). Targeted sequencing of ROBO4 showed enrichment for rare variants in probands with BAV and ascending aortic aneurysm compared with controls: collectively, among familial and individual probands, 13 (1.77%) of 736 had a ROBO4 variant that passed a priori filtering constraints, whereas 1 rare missense variant was observed among 376 'rigorously phenotyped' controls (2-tailed Fisher exact test, p = 0.0432). One of the independent probands carried the same R64C missense variant that was identified in family 2; clinical details were not reported for that patient.